In modern animal agriculture, genetic selection for intense production have created animals that produce food for mankind at a rate beyond the capabilities of their traditional metabolic machinery's capacity. This is particularly true during the time around parturition, when exponential fetal growth, compromised gut fill capacity, and pending lactation demands combine to create an energy shortage. This nutritional energy stress and related shortage is evidenced as various disease states in many species, for example, ketosis and retained placenta in cattle.
Ketosis is a metabolic disease that usually occurs in early lactation and is characterized by elevated levels of ketone bodies in the body fluids. Clinical signs include reduced appetite, reduced milk production, reduced carbohydrate status, weight loss and hypoglycaemia. Since the time when the disease was first diagnosed, it has been assumed that the underlying cause of ketosis was the shortage of glucose supply relative to demand. Researchers, however, have questioned the accuracy of the glucose shortage theory. Schultz, L. H. and Smith, V. R. note that a deficiency of blood glucose alone does not appear sufficient to cause ketosis in ruminants (J. Dairy Sci., Vol.34, (1951), p.1190). Shaw, J. C. notes that theories on the etiology of ketosis do not explain how a cow can be hypoglycaemic in early lactation without being ketotic (J. Dairy Sci., Vol.39 (1956), p.402).
The glucose shortage theory proposes that the mammary gland of the ruminant has a high degree of precedence in its demand for glucose. The mammary gland can deplete blood glucose and hepatic precursors of glucose. This results in gluconeogenesis, i.e. the metabolic formation of glucose from gluconeogenic compounds such as propionate, and this high mammary demand also leads to the release of free fatty acids (FFA), also referred to as non-esterified fatty acids (NEFA), from the adipose tissue. The liver is unable to completely oxidize all the NEFA entering it and hepatic ketogenesis occurs.
A different view of the cause of ketosis has been presented by D. S. Kronfeld (Kronfeld, D. S. "Homeostatic Disorders Associated With Lactation", Bovine Medicine and Surgery, Chpt.11, pp.539-565). This theory postulates that spontaneous ketosis is due to an insufficiency of lipogenic nutrients relative to glucose.
This competing theory espoused by Kronfeld postulates that there is actually too much glucose in relation to lipogenic substances in the blood and the mammary gland calls for the release of NEFA from the adipose tissue.
The treatment of ketosis has primarily relied on increasing the quantity of glucose available for utilization by the ruminant's tissues. This has been accomplished by providing the liver with gluconeogenic compounds or by directly infusing glucose into the blood stream. Glucose therapy, however, has not shown itself to be the only therapy needed. Frustration with glucose therapy has been the main reason for trying other treatments. The administration of glucose precursors such as sodium propionate, lactate, glycerol or propylene glycol is followed by less dramatic and consistent improvement than is expected from glucose. The glucose precursors or gluconeogenic compounds are then processed into glucose by the liver. These treatments have been useful only therapeutically and not in all cases. Consequently, glucose precursors are not viewed as sole or primary therapy for mild or severe cases. Usually, the cow will often correct its own energy imbalance eventually by reducing milk output.
It has been proposed, as an alternative to the glucose shortage concept, that ketosis in cattle develops when there is an excess of gluconeogenic nutrients in the ration relative to the lipogenic nutrients. The fat precursors can either be supplied directly from the diet or from body stores. If the lipogenic substances are mobilized from body stores, ketosis may develop. Therefore, it has been proposed by Kronfeld and Chalupa that in order to prevent ketosis, fatty acids of a chain length of 14 or more carbons should be included in the diet, thus, preventing the need to mobilize depot fat (Animal Nutrition and Health, November-December 1983 p.28). Long chain fatty acids mobilized from fat stores are present as free fatty acids in the blood which are extracted by the liver and are highly ketogenic. In contrast, long chain fatty acids that bypass the rumen are absorbed from the small intestine into the lymph in the form of chylomicrons. These are not extracted by the liver and are not ketogenic in ruminants. Therefore, it has been proposed that the kinds of fats that should be fed to prevent ketosis should have fatty acids of a chain length of 14 or more carbons and should be inert to the rumen.
Although fat is a well recognized storage form of energy, animals can not make glucose from fat. The energy precursors derived from fat breakdown can only be processed to energy when carbohydrate degradation is happening in a parallel and balanced manner. If fat degradation predominates over carbohydrate availability, the fat breakdown entities undergo a different fate, specifically, to ketone bodies.
The Krebs Cycle or citric acid cycle in mammals is the common final pathway for the oxidation of molecules such as amino acids, fatty acids and carbohydrates. Fatty acids are oxidized to acetyl CoA (AcCoA). The two carbon acetyl CoA enters the citric acid cycle only if there is sufficient oxaloacetate (OAA), a four carbon molecule. OAA and AcCoA combine to form citrate, a six carbon acid that is enzymatically passed around the Krebs Cycle, finally regenerating OAA and energy. OAA is not formed in the process, only regenerated, thus its availability is rate limiting for the amount of energy derived from the citric acid cycle. OAA is also used for glucose production from other glucose precursors such as amino acids.
At the time of parturition many systems have dramatically increased energy need. The organism's response is to mobilize body stores of fat. But, mammals cannot convert acetyl CoA into pyruvate or OAA. To obtain energy from fat, this fat typically goes to the liver for processing. With only limited OAA, the sudden influx of mobilized fatty acid metabolites overwhelms the supply of OAA and ketones are produced as an emergency solution. This situation is greatly exacerbated by the fact that OAA also is an obligate intermediate for gluconeogenesis, so an already compromised OAA pool is still further lessened by the driving need for glucose. There simply just isn't enough OAA to process mobilized fat and support glucose synthesis.
The metabolic condition of the parturient cow is summarized below:
1. An overall energy (glucose) deficit has caused the liver to maximize glucose synthesis from all available precursors via the process of glycogenesis. PA0 2. This same energy deficit has elicited the release of stored energy from body reserves, resulting in a high mobilization of fatty acid. PA0 3. Ruminants can not make glucose from this mobilized fat; it only represents an aid in the energy crisis because it can be oxidized for ATP, the same ultimate contribution of glucose. PA0 4. The liver has two critical functions pertinent to the energy crisis; make glucose for tissue consumption and process AcCoA from fatty acid oxidation for energy. PA0 5. Oxaloacetate (OAA) is an essential component for the execution of both of the needed functions of the liver in this energy crisis. PA0 6. The liver preferentially uses OAA for glucose production driven by the high and immediate need for glucose by the conceptus mass, birthing, and pending lactation. PA0 7. The diversion of OAA to gluconeogenesis compromises the citric acid cycle, which also needs OAA to function. PA0 8. In the absence of OAA, what AcCoA enters the liver mitochondria citric acid cycle is processed into ketone bodies. While many tissues can eventually utilize ketones for energy, this requires a 48 to 72 hour adaptation period, and before this time, the accumulated ketones and energy shortage induce a malaise that depresses appetite. PA0 9. Depressed appetite further complicates the energy crisis, and a downward spiral ensues. PA0 1. Dietary fat is presented to the energy deficit tissues without involving the liver which helps provide for the overall energy needs of the tissue and tends to lessen the hormone signals triggering fat mobilization. PA0 2. Less mobilized fat reduces the flooding of the liver with fat and lowered ketone production results. PA0 3. Gluconeogenic precursors provided by the composition of the invention augment the production of glucose. PA0 4. The preceding benefits (direct energy to the tissue; less fat sent to the liver and therefore less ketones; more gluconeogenesis, therefore still more glucose for the tissues) combine synergistically to prevent malaise and appetite loss. PA0 5. With the foregoing benefits, the dam "feels better" by virtue of the elimination of negative circumstances. PA0 6. By feeling better, and with the prevention of a depressed appetite, the dam eats more. Greater dry matter intake further addresses her energy shortage in a positive way. PA0 7. The feeding of the composition to ruminants results in not only a prevention of production losses, but enables higher production than normal .
Microbial fermentation of a ruminant's feedstuff occurs in the rumen. Further digestion occurs in the abomasum. U.S. Pat. No. 5,182,126 to Vinci et al. discloses a feed supplement which contains a C.sub.14 -C.sub.22 fatty acid alkaline earth metal salt and a biologically active ingredient which functions as a rumen bypass animal feed supplement and increases dietary fat in the feed. A feed additive such as a fatty acid alkaline earth metal salt functions as a rumen inert product which passes through the rumen. Such products are known as rumen bypass products. The alkaline earth metal salt is not very palatable to the ruminant. The feed product of this prior art, however, functions as a rumen bypass composition. Thus, the propionate gluconeogenic ingredient is not available to the rumen or rumen microbes for digestion, fermentation, or metabolization.
Ferre, P., Pegorier, J. P., Marliss, E. B. and Girard, J. R. disclose that orally feeding fat and injecting gluconeogenic substrates to starved, neonatal rats reverses hypoglycaemia (Am. J. Physiol. 234(2): E129-136). The use of injection makes such a treatment onerous for treating larger animals. Unlike cows, starved neonatal rats do not have energy stores to mobilize, thus, the complications with treating cows are not evident.
It is desirable to be able to treat or prevent an energy imbalance disorder, such as ketosis, by providing gluconeogenic precursors in the rumen and by bypassing lipogenic nutrients through the rumen and into the lower digestive tract for absorption as chylomicrons, thereby providing an improved treatment over the prior art.